Recent advances in biomedical research and high-throughput drug screening have generated numerous potential therapeutics for the treatment of CNS related illnesses. However, many therapeutics fail in vivo testing because of inadequate transport through the blood-brain barrier (BBB).
Therapeutics can cross the BBB using several pathways, including saturable transporter systems, adsorptive transcytosis wherein the therapeutic to be transported is internalized by a cell in the BBB and routed to the abluminal surface for deposition into the brain intracellular fluid compartment, transmembrane diffusion wherein the therapeutic dissolves into the lipid bilayer which forms the membranes of the cells comprising the BBB, and extracellular pathways wherein the therapeutic exploits the residual leakiness of the BBB.
Several approaches to modify therapeutic agents to alter their BBB permeability have been attempted, including conjugation with proteins that naturally cross the BBB, for example insulin, insulin-growth factor 1 and 2 (IGF-1, IGF-2), leptin and transferrin (US Pat. Appl. No. US2007/0081992), linking the polypeptides to cationized antibodies binding to certain cellular receptors, such as insulin receptor (U.S. Pat. No. 7,388,079) or transferrin receptor (U.S. Pat. No. 6,329,508; Zhang and Pardridge, Brain Res. 889:49-56, 2001); coupling the therapeutics with synthetic polymers such as poly(butyl cyanoacrylate) or polyacrylamide covered with Polysorbate 80 (US Pat. Appl. No. 2002/0009491, US Pat. Appl. No. 2002/0013266; US Pat. Appl. No. 2006/0051317), and using liposomes or immunoliposomes.
The current approaches to improve the transport of therapeutic agents across the BBB include ineffectiveness due to competition with the endogenous ligand, lack of transport of the therapeutic to brain parenchyma, and degradation of the therapeutics due to lysosomal targeting.
Thus, there is a need to develop methods to transport therapeutic agents through the BBB.